A variety of imperfect techniques are available to assess human exposure to chemicals. Detection of environmental levels of chemicals by means of, for example, air sampling devices fails to yield information on actual extent of body exposure e.g., actual entry into the body. Most known techniques for assessing the actual extent of body exposure to chemicals suffer from their invasiveness (e.g. tissue biopsies, blood sampling) or their impracticality (e.g. collection of urine or saliva). With the exception of continuous urine collections, most known systems do not provide information on cumulative exposure over a period of time.
A system which addresses the need to provide detection of a drug material with correlation with time in order to obtain useful information concerning drug absorption, excretion, metabolism rates and metabolites is described in U.S. Pat. No. 3,649,199 to D. P. Littlejohn; however, attachment of the patient to the analytical instrumental is required. This patent describes a method for detecting trace quantities of an organic drug material in a living animal which involves passing a sample of gaseous material effusing from the animal by breath, through the skin or from the blood stream through a multi-stage membrane gas separator to enrich the concentration of the organic drug material in the gaseous sample. The enriched sample gas output of the membrane separator is fed to a gas analyzer such as a mass spectrometer for detection of the organic drug material. This patent describes the obtention of a sample of gaseous material from a region immediately adjacent the skin of the animal by means of a gas impervious sleeve clamped to the forearm of a person for the containment of a carrier gas such as nitrogen or helium.
U.S. Pat. No. 3,552,929 to R. P. Fields et al. describes a device for detecting halide ion concentration in a fluid such as human perspiration for the diagnosis of cystic fibrosis. The device is used in conjunction with an absorptive sweat collection patch which is described as a piece of filter paper under a polyethylene overlayer to prevent evaporation.
U.S. Pat. No. 4,329,999 to M. Phillips is directed to a clinical test device more specifically described as a sweat collection patch for monitoring a human patient for the presence of sweat-excreted drugs such as alcohol. Other drugs such as digoxin, lithium, anti-convulsants, or morphine excreted in sweat are also disclosed as detectable by the patch but no specific details or experiments are provided. The patch device according to this patent is disclosed as inexpensive, easy to use, non-intrusive and capable of yielding accurate and precise measurements in that the patch is capable of collecting sweat in a continuous manner and at a steady rate. The circular shaped patch is described as including a backing member, a stripping member, a base, a collecting pad and a cover member having an adhesive surface contiguous to the collecting pad. This patent further discloses that the collecting pad includes a plurality of layers of polyester-type absorbent material formed by a certain method including thoroughly wetting the polyester with a saturated aqueous solution of sodium chloride and subsequently causing the precipitation of sodium chloride in the polyester material The discs formed from the dried polyester are then wetted with a solution, preferably containing Nystatin, sodium fluoride and reduced methylene blue. This patent discloses that the Nystatin is used to inhibit fungal proliferation since fungi could cause metabolic breakdown of ethanol and/or metabolic breakdown of glucose in sweat to ethanol and methanol. The sodium fluoride is described as inhibiting anaerobic glycolysis in bacteria and fungi and hence the production of ethanol. The reduced methylene blue is used as a visual indicator when the patch is removed since in a wet patch it turns bright blue in the presence of oxygen. This patent further discloses that magnesium sulfate, fructose or urea may be used in lieu of sodium chloride in that this patch element must be an osmotically active highly soluble crystalloid.
The patch according to this patent is said to yield for drug assay virtually all of the collected sweat when, presumably, the pad of the patch is spun in a specially constructed centrifuge tube. The reverse flow of sweat from the absorbent pad in the cover member chamber through the base member is described as controlled by the relative size and orientation of the base member hole and the chamber containing the pad which is said to permit sweat to easily enter the absorbent pad but inhibit the reverse flow of sweat out of the chamber.
An earlier sweat collecting device is described in M. Phillips, R. E. Vandervoort and C. E. Becker, "Long-term Sweat Collection Using Salt impregnated Pads"; J. Invest. Dermatol., 68:221-224 (1977). The pad described therein was a square cut from a commercially available disposable diaper material consisting of a layer of absorbent cotton sandwiched between a sheet of waterproof polyurethane on one side and two layers of porous, woven rayon on the other. Both sodium chloride impregnated as well as control pads were prepared. The device incorporating this pad was constructed by applying to the patient an adhesive template, then placing the pad over the template, covering the pad with a square of this plastic sheet and thereafter sealing the assembled device in place on the patient with a square of waterproof adhesive tape.
The foregoing work, inter alia, is referred to in C. C. Peck, M. Phillips, C. E. Becker and K. L. Melmon "Drug Measurement in Sweat: A New Approach in Clinical Pharmacology", Abstracts, Fifth Pharmacology-Toxicology Program Symposium, National Institute of General Medical Sciences, p. 29; (1977).
The authors, noting problems created by intermittent or erratic alcohol ingestion, disclosed the undertaking of a theoretical analysis to determine technical requirements for an optimal sweat collection device which involved mathematical simulation of the dynamics of a drug in sweat assuming drug disposition with one compartment, zero or first-order excretion kinetics and first-order transfer of drug between the body and the sweat collection device. The authors disclose the conclusion that (1) sweat flow into the device must be continuous and constant, (2) drug losses from the device, both external and back-transfer into the body, must be minimized, (3) drug bound in the device must be extractable for qualitative analysis, and (4) the sweat collection device should be small (&lt;2 cm.sup.2), safe, and acceptable to the subject being studied. It is stated that development of a suitable sweat collection device may contribute particularly to the study of bioavailability, to the clinical assessment of compliance with therapeutic regimens, and to the diagnosis of addictive states such as alcoholism.
A later article by M. Phillips, "An Improved Adhesive Patch For Long-Term Collection of Sweat", Biomat., Med. Dev., Art. Org., 8(1), 13-21 (1980), refers to the practical limitations of the adhesive skin patch of the above-referred to M. Phillips et al. 1977 article and describes the structure and structure and evaluation of an improved adhesive patch similar in some respects to that described in U.S. Pat. No. 4,329,999 to M. Phillips. The use of soluble crystalloid material such as sodium chloride, magnesium sulfate, urea, fructose and sucrose is disclosed. The adhesive patch device of the M. Phillips et al. 1977 article was also referred to in C. C. Peck et al., "Continuous Transepidermal Drug Collection:Basic for Use in Assessing Drug Intake and Pharmacokinetics", J. Pharmacokinetics and Biopharmaceutics 9(1):41-58 (1981) which report explores a theoretical basis for the use of transepidermal drug collection in assessing various aspects of drug pharmacokinetics, with emphasis on its use in the quantitation of cumulative amount of drug exposure. The influence and implications of single and polyexponential drug disposition kinetics; zero-, first-order, and Michaelis-Menten excretion functions; and back transfer of drug from the collection device were explored.
The M. Phillips et al. 1977 article and the M. Phillips 1980 article Were also referred to in C. C. Peck et al. "Mechanism of Noninvasive Collection of Substances Dissolved in Interstitial Fluid", Clinical Research, Vol. 30, No. 2 (256A) April 1982. This excerpt reports test of the hypothesis that the transepidermal fluid collection method according to M. Phillips can be used to collect substances dissolved in interstitial fluid by application to rabbits, a species without sweat glands. Collection devices according to the Phillips 1980 paper were tested on the rabbits for detection of .sup.22 Na with observations leading to postulation of a mechanistic theory of transepidermal fluid collection of non-volatile substances dissolved in interstitial fluid: (1) pre-wetting the Phillips pads leads to hydration of stratum corneum, thus increasing its permeability to substances in the interstitial fluid; (2) hydrated stratum corneum acts as a semi-permeable membrane separating two aqueous regions; (3) movement of substances from interstitial fluid across stratum corneum into the Phillips collection device follows thermodynamic principles. Peck et al. conclude that this theory is consistent with that postulated previously by Peck et al. (1981) and should be tested in man.
The device of the Phillips (1980) article as well as the theoretical analysis of Peck et al. (1981) was also treated in C. C. Peck et al., "A Noninvasive Transepidermal Toxicological Monitoring Device", Pittsburgh Conference and Exposition on Analytical Chemistry and Applied Spectroscopy, p. 366 Abstract, 1982. Therein is disclosed the modification of a Phillips experimental prototype transepidermal fluid collection device by the insertion of an activated charcoal cloth or a Teflon disk, on which is impregnated activated charcoal, between the pads of the collection device. The abstract discloses that incorporation of activated charcoal into the device retards back-transfer of theophylline by an average of 50% but results were variable. The abstract concludes with the statement that improvements in the adhesiveness, water-tightness and other structural features of the device are required in order to reduce the variable uptake and binding of theophylline and that reliable xenobiotic uptake and prevention of back-transfer may lead to extension of the utility of transepidermal fluid collection from qualitative to quantitative surveillance of human exposure to xenobiotics.
Other dermal patch devices are known which differ in components and which serve different purposes than the device of this invention. One is a drug delivery device comprising a drug-containing polymeric diffusion matrix which can be applied as a transdermal patch with means for fastening the matrix to the skin of a person as disclosed in U.S. Pat. No. 4,321,252. Another is what appears to be an adhesively attachable electrode for monitoring vital signs. The metal electrode projects through a molded plastic shell which contains a rather porous sponge-like packing with a liquid substance, presumably containing an electrolyte. The shell is encircled by an attached ring of a form substance having an adhesive surface for dermal attachment.
Similarly, in the context of ease of application, the discovery of the dermal substance collection device according to this invention makes available means for the convenient, non-invasive, immediate and continuous collection of a chemical substance from a body's dermal surface by simple application of the device thereto.